Therapeutic Drug Monitoring of Antibiotics

The aminoglycoside antibiotics consist of two or more aminosugars joined by a glycosidic linkage to a hexose or an aminocyclitol. Streptomycin was the first aminoglycoside discovered in 1914. These drugs are used in the treatment of serious and often life-threatening systemic infections. However, aminoglycoside can produce serious nephrotoxicity and ototoxicity. Peak serum concentrations for amikacin and kanamycin above 32-34 ^g/mL are associated with a higher risk of nephrotoxicity and ototoxicity (137). Sustained peak concentrations above 12-15 ^g/mL are associated with an increased risk of developing nephrotoxicity and ototoxicity for gentamicin, tobramycin, and sisomicin. For netilmicin, the toxicity is encountered at a peak concentration above 16 ^g/mL. Peak concentration of streptomycin should not exceed 30 ^g/mL (138).

Aminoglycosides are poorly absorbed from the gastrointestinal track, and these drugs are administered intravenously or intramuscularly. The major route of elimination is through the kidney where 85-95% of the drugs are recovered unchanged. Patients with impaired renal function have lower aminoglycoside elimination rates and longer half-lives compared with patients with normal renal function. Moreover, elimination of aminoglycosides is slower in elderly patients, and many patients require prolonged dosing interval. Children have a higher clearance of aminoglycosides. Siber et al. reported that after 1 mg/kg dose of gentamicin, the mean peak plasma concentration was 1.58 ^g/mL in children with age between 6 months and 5 years, 2.03 ^g/mL in children between 5 and 10 years, and 2.81 ^g/mL in children older than 10 years. Patients with fever showed shorter half-life and lower plasma concentrations of gentamicin (139).

Patients with cystic fibrosis usually exhibit an altered pharmacokinetics of the antibiotics. After a conventional dose of an aminoglycoside, a patient with cystic fibrosis shows a lower serum concentration compared with a patient not suffering from cystic fibrosis. The lower serum concentrations of aminoglycoside in patients with cystic fibrosis may be due to increased total body clearance of these drugs combined with a larger Vd (140). Bosso et al. reported that mean clearance of netilmicin was higher in patients with cystic fibrosis compared with that in patients with no cystic fibrosis. Therefore, patients with cystic fibrosis required larger than normal dosages of netilmicin on a weight basis. The study also showed that the serum concentrations of netilmicin should be monitored carefully to individualize dosage in these patients (141). Another study indicated that the major route of elimination of gentamicin in patients with mild cystic fibrosis is through renal excretion, but aminoglycoside pharmacokinetics were changed with progression of disease (142). Mann et al. (143) reported increased dosage requirement for tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis. Dupuis et al. observed significant differences in pharmacokinetics of tobramycin in patients with cystic fibrosis before and after lung transplantation in a group of 29 patients who received at least one dosage of tobramycin before and after lung transplant. The clearance of tobramycin was decreased by 40% and the half-life was increased by 141% after transplant compared with pre-transplant values (144). Patients with cystic fibrosis are also susceptible to renal impairment from repeated intravenous use of aminoglycosides, and these drugs should be cautiously used in these patients with regular monitoring of renal function (145).

Renal clearance of penicillin is enhanced in cystic fibrosis because of the greater affinity of the renal secretory system for these drugs (146). Another study involving 11 patients with cystic fibrosis and 11 controls demonstrated that mean elimination halflife of ticarcillin in serum was 70.8 min in control subjects and 53.1 min in subjects with cystic fibrosis. The non-renal clearance of ticarcillin was also higher in patients with cystic fibrosis compared with that in controls. The authors concluded that the shorter elimination half-life and higher total body clearance of ticarcillin in patients with cystic fibrosis are because of an increase in both renal and non-renal elimination (147).

Therapeutic drug monitoring is also frequently employed during vancomycin therapy. The drug is excreted in the urine with no metabolism, and there is no known pharmacogenetic problem. Vancomycin has a low therapeutic index with both nephrotoxicity and ototoxicity complicating the therapy (148). It is necessary to monitor both peak and trough concentration of vancomycin. Ranges for peak concentrations of 20-40 ^g/mL have been widely quoted (149). The given trough range of 5-10 ^g/mL has reasonable literature support. Trough concentration above 10 ^g/mL has been associated with an increased risk of nephrotoxicity (150,151). For infants, Tan et al. recommended a conservative therapeutic range of 5-10 ^g/mL for the trough and 20-40 ^g/mL for the peak concentration. A less conservative range is 5-12 ^g/mL for trough and 15-60 ^g/mL for peak (152). However, de Hoog et al. (153) recommended a trough concentration between 5 and 15 ^g/mL and a peak concentration below 40 ^g/mL in neonates. Zimmermann et al. (154) reported that patients were more likely to become afebrile within 72 h if the peak and trough vancomycin concentrations were greater than 20 and 10 ^g/mL, respectively. Although the dispositions of many antibiotics are altered in patients with cystic fibrosis, patients with cystic fibrosis exhibit a disposition of vancomycin similar to that exhibited by healthy adults, and thus, cystic fibrosis does not alter pharmacokinetic parameters of vancomycin (155). Reference ranges and costs for monitoring antibiotics are summarized in Table 10.

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